Intravenous baclofen formulations and treatment methods

ABSTRACT

An intravenous baclofen solution is disclosed, along with methods of dosing and treatment therewith.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/997,135, filed 15 Jan. 2016 (the '135 application), which claims thebenefit of U.S. provisional application No. 62/103,902, filed 15 Jan.2015 (the '902 application). The '135 application and the '902application are both hereby incorporated by reference in their entiretyas though fully set forth herein.

BACKGROUND OF THE INVENTION

Baclofen is a muscle relaxant and anti-spastic agent. Spasticity is acommon symptom of upper motor neuron injury in individuals with cerebralpalsy, multiple sclerosis, acquired spinal cord injury, brain injury,and neurodegenerative disorders. Baclofen is a structural analog of theinhibitory neurotransmitter gamma-aminobutyric acid (GABA) and acts as aGABA_(B) agonist at the level of the spinal cord. Baclofen is thegeneric name for 4-amino-3-(4-chlorophenyl) butanoic acid. It is a whiteor off-white, mostly odorless crystalline powder with a molecular weightof 213.66, and it is slightly soluble in water. Baclofen's structuralformula is

Baclofen is sold under the tradename LIORESAL® in oral (10 mg or 20 mgtablets) and intrathecal (0.05 mg/mL, 0.5 mg/mL, or 2.0 mg/mL)formulations. The intrathecal formulation is used in conjunction with animplanted programmable pump to provide a constant infusion of the drug.There are several circumstances in which patients treated with oral orintrathecal baclofen must abruptly discontinue therapy. For example, theprogrammable pump and/or catheter used in intrathecal administration mayneed to be removed, refilled, or replaced. Moreover, patients takingoral baclofen may be unable to do so during periods of illness,noncompliance, or surgery, for example. Abrupt discontinuation of oralor intrathecal baclofen can result in a severe withdrawal syndromecharacterized by rebound increases in muscle tone and spasms, statusepilepticus, hallucinations, and a neuromalignant syndrome-like picturepotentially resulting in rhabdomyolysis and multisystem organ failure.The current recommended management of baclofen withdrawal is inadequate,and symptoms are often difficult to control. Agarwal et al., A PilotStudy Assessing Pharmacokinetics and Tolerability of Oral andIntravenous Baclofen in Healthy Adult Volunteers, J Child Neurol., (Jul.14, 2014),http://jcn.sagepub.com/content/early/2014/07/11/0883073814535504.

Thus, there is a clinical need for an intravenous baclofen formulationto prevent or minimize complications resulting from interrupted oral orintrathecal therapy.

BRIEF SUMMARY OF THE INVENTION

An intravenous baclofen solution is disclosed, along with methods ofdosing and treatment therewith. It is believed that intravenousadministration of baclofen can permit rapid attainment of necessary drugconcentrations, as well as accurate and precise dose titration, therebyallowing for more efficient and effective treatment of withdrawalsymptoms or preventing withdrawal altogether.

One embodiment of the invention provides a method of temporarilytreating a subject with baclofen during a period of medical fluctuationthat comprises (a) discontinuing oral or intrathecal administration ofbaclofen to the subject; (b) administering to the subject a bolusintravenous dose of a therapeutically effective amount of a solutioncomprising baclofen at a concentration of up to about 2.0 mg/mL over atime period of about 5 minutes to about 60 minutes; (c) repeatingadministration of the bolus intravenous dose of baclofen about every 6to 8 hours until oral or intrathecal administration of baclofen can beresumed; (d) discontinuing administration of bolus intravenous doses ofbaclofen; and (e) resuming oral or intrathecal administration ofbaclofen.

In another embodiment, a method of intravenously administering baclofento a subject that has previously been treated with oral baclofen in atherapeutically effective amount comprises (a) discontinuing oraladministration of baclofen to the subject; (b) administering to thesubject a bolus intravenous dose of solution comprising about 75% ofsaid amount of baclofen over a time period of about 5 minutes to about60 minutes; (c) repeating administration of the bolus intravenous doseof baclofen about every 6 to 8 hours until oral administration ofbaclofen is resumed; (d) discontinuing administration of intravenousbaclofen; and (e) resuming oral administration of baclofen.

In another embodiment, a method of temporarily treating a subject withbaclofen during a period of medical fluctuation comprises (a)discontinuing oral or intrathecal administration of baclofen to thesubject; (b) starting a continuous intravenous infusion of atherapeutically effective amount of a solution comprising baclofen at aconcentration up to about 2.0 mg/mL over a time period of about 24hours; (c) continuing the infusion about every 24 hours until oral orintrathecal administration of baclofen is resumed; (d) discontinuing thecontinuous intravenous infusion; and (e) resuming oral or intrathecaladministration of baclofen.

In another embodiment, a method of intravenously administering baclofento a subject that has previously been treated with oral baclofen in atherapeutically effective amount comprises (a) discontinuing oraladministration of baclofen to the subject; (b) administering acontinuous intravenous infusion of solution comprising about 75% of saidamount of baclofen over a time period of about 24 hours; (c) continuingthe infusion about every 24 hours until oral administration of baclofenis resumed; (d) discontinuing administration of the continuousintravenous infusion; and (e) resuming oral administration of baclofen.

In another embodiment, a method of converting an oral dose of baclofento an intravenous dose of baclofen comprises (a) determining the oraldose; and (b) multiplying the oral dose by between about 0.45 and about1.0 to determine the intravenous dose.

In another embodiment, a pharmaceutical solution comprises an effectivetherapeutic amount of up to about 2.0 mg/mL baclofen dissolved in atleast one of normal saline, dextrose solution, Lactated Ringer'ssolution, or any combination thereof; wherein the solution is adapted tobe intravenously administered to a subject.

DETAILED DESCRIPTION OF THE INVENTION

Each milliliter of intravenous baclofen solution can contain about 0.5mg to about 2.0 mg of baclofen and an isotonic amount of sodium chloridedissolved in sterile water. In an embodiment, the concentration ofbaclofen in the intravenous solution can be about 0.5-2.0 mg/mL. In anembodiment, the intravenous baclofen solution can include a dextrosesolution or Lactated Ringer's solution instead of or in combination withnormal saline. The intravenous baclofen solution can further include ananticonvulsant drug, an antispasmodic drug, an anticholinergic drug,and/or an antibiotic.

The present invention also provides a correlation between oral andintravenous dosing of baclofen (see, e.g., Example 2 below). Inparticular, an equivalent dose of intravenous baclofen can be determinedby multiplying the oral dose of baclofen by about 0.45 to about 1.0,preferably by about 0.6 to about 0.9, and more preferably by about 0.75.

Generally, an effective amount of the above-described intravenousbaclofen solution can be administered intravenously to temporarily treata patient during a period of medical fluctuation resulting in thediscontinuation of oral or intrathecal baclofen. Temporary treatmentwith intravenous baclofen may be necessary as bridging therapy (e.g.,when a patient is temporarily unable to take oral or intrathecalbaclofen) or for management of withdrawal symptoms, for example. As usedherein, a “period of medical fluctuation” refers broadly to a timeperiod during which a patient experiences an illness, condition, changein health status, or situation requiring an adjustment to his/her normalmedical care or treatment plan. More specifically, a period of medicalfluctuation can include at least one of a scheduled or unscheduledsurgical procedure, trauma, ileus, bowel obstruction, vomiting,diarrhea, gastrointestinal malabsorption, seizure, stroke, subarachnoidhemorrhage, or patient noncompliance. Furthermore, for patients withimplanted intrathecal pumps, periods of medical instability can includean intrathecal hardware failure or a necessity to remove, refill, orreplace the intrathecal hardware.

In one embodiment of the invention, a method is provided to temporarilytreat a patient with intravenous baclofen during a period of medicalfluctuation that comprises discontinuation of oral or intrathecaladministration of baclofen to the patient, followed by administration ofan intravenous bolus dose of a therapeutically effective amount of abaclofen solution (e.g., between about 1 mg and about 50 mg baclofen perbolus dose) over a time period of about 5 to 60 minutes. The intravenousbolus dose can be administered repeatedly about every 6 to 8 hours untiloral or intrathecal administration of baclofen can be resumed. Onceintravenous bolus doing has been discontinued, oral or intrathecaladministration of baclofen can be resumed.

In another embodiment of the invention, a method of temporarily treatinga patient with intravenous baclofen during a period of medicalfluctuation is provided that can include discontinuation of oral orintrathecal administration of baclofen, followed by administration of acontinuous intravenous infusion of a therapeutically effective amount ofa baclofen solution continued until oral or intrathecal administrationof baclofen can be resumed. Once continuous intravenous infusions havebeen discontinued, oral or intrathecal administration of baclofen can beresumed. It is believed that continuous intravenous infusion of baclofencan mimic intrathecal administration of baclofen, can eliminate ormitigate any peaks or troughs in baclofen levels in a patient's cerebralspinal fluid or blood (which may occur during intravenous bolusadministration, for example), and can reduce the risk or incidence ofadverse events associated with intravenous baclofen.

The invention will be further described by the following detailedexamples.

Example 1 Preparation of Intravenous Baclofen Solution

108 g of sodium chloride were placed in a 600 ml beaker and then addedto a 20 L beaker containing 8.4 L of sterile water for injection. Theresulting sodium chloride solution was stirred in the 20 L beaker untildissolution occurred. Approximately 50 ml of sterile water for injectionwere used to rinse any residual sodium chloride from the 600 ml beaker,and the rinsings were added to the 20 L beaker. Next, 24.1 g of baclofenpowder were placed in a 1 L beaker and then gradually (over a timeperiod of about 2 hours) added and dissolved in the solution in the 20 Lbeaker. Approximately 50 ml of sterile water for injection was used torinse any residual baclofen from the 1 L beaker, and the rinsings wereadded to the 20 L beaker. Approximately 3500 mL of sterile water forinjection were then added to the 20 L beaker, and the solution was mixedfor a minimum of 10 minutes to ensure homogeneity. The solution was thenfiltered using a Mini Kleenpak™ (0.2 μm) filter at 20 rpm.

An automated, aseptic filling machine was used to fill approximately1090 13.5-mL glass vials with approximately 11.0 ml of the solution pervial. The vials were then stoppered, caps were placed on the vials, andthe caps were crimped. The vials were stored at about 15 degrees Celsiusto about 25 degrees Celsius.

Example 2—Administration of Intravenous Baclofen

A. Subjects

Twelve healthy human volunteers were recruited. The volunteers weremedication free for 48 hours before, during, and 24 hours after theadministration of the study drug.

B. Study Design

The 12 volunteers participated in a randomized, open-label, 2-waycrossover study to compare the pharmacokinetics and bioavailability oforal baclofen with an intravenous baclofen formulation. The oralformulation was a 10 mg baclofen tablet. A single intravenous dose of 5mg was administered over 15 minutes, using the commercially available 2mg/mL intrathecal baclofen formulation (Lioresal Intrathecal). Bloodsamples (6 mL) for the measurement of plasma concentrations of baclofenwere collected in blood collection tubes containing K2ethylenediaminetetraacetic acid at the following times: prior to dosing;at 5, 15, and 30 minutes; and at 1, 2, 4, 6, 8, 10, 12, and 24 hoursafter drug administration.

C. Determination of Baclofen Concentration in Plasma

Study plasma samples were prepared by adding 50 μL of a 500 μg/mLlevetiracetam solution (internal standard) to 250 μL of K2ethylenediaminetetraacetic acid (EDTA) human plasma. Baclofen and theinternal standard were extracted from plasma by precipitating theprotein with methanol and drying it under nitrogen at approximately 40°C. The dried residues were reconstituted in 300 μL of a mobile phaseconsisting of 20 mM ammonium acetate-methanol (75:25) solution. After 1minute of vortex mixing, the reconstituted sample solution was filteredand injected onto the high-performance liquid chromatograph-massspectrometer system. Standard curve samples over a range of 20 to 400ng/mL baclofen and quality control samples containing 30 (low), 80(medium), and 240 ng/mL (high) baclofen were prepared and analyzed intriplicate along with the study samples. The assay was linear over therange 20-400 ng/mL with a lower limit of quantification of 20 ng/mL.

Baclofen concentration-time data were analyzed using a noncompartmentalpharmacokinetic approach with Phoenix software (version 6.2; PharsightCorporation, Mountain View, Calif.). The terminal rate constant (λz) wasdetermined from the slope of the terminal log-linear portion of theplasma concentration-time curve, and the terminal half-life (t_(1/2))was calculated as In 2/(λz). Maximum plasma concentrations (C_(max)) andtime to maximum concentration (T_(max)) were determined by directobservation of the data. The area under the concentration-time curve tothe last nonzero plasma concentration (C_(last)) that was above half thelower limit of quantification (10 ng/mL) was calculated by thetrapezoidal rule and reported as AUC_(last). The area under theconcentration-time curve extrapolated to infinity (AUC_(0-∞)) wascalculated as AUC_(last)+(C_(last)/λz). Mean and standard deviationvalues for the parameters were also obtained using the descriptivestatistics tool in Phoenix version 6.2. A paired t-test was used todetermine if statistical differences existed in log normalized,dose-adjusted area under the curve between oral and intravenous arms.

D. Results

A summary of the pharmacokinetic parameters is presented in Table 1. Themean concentration-time profiles for both (5 mg intravenous and 10 mgoral) arms are shown in FIG. 1. When the subjects received theintravenous formulation, the observed maximum baclofen concentrationoccurred at the 5-minute time point, whereas the median Tmax for oraladministration was 1 hour. The mean (standard deviation) Cmax values forthe oral (10 mg) and intravenous (5 mg) doses were 176 (15) ng/mL and313 (75) ng/mL, respectively (FIG. 1). The mean t_(1/2) was similar forboth the oral and intravenous arms (4 and 4.52 hours, respectively). Themean absolute bioavailability of the oral baclofen tablets (Table 1) was74%. There was a significant difference in log-normalized, dose-adjustedarea under the curves (P=0.0024) between oral and intravenous dosingwith similar variability (coefficient of variation: 18%-24%).

TABLE 1 Mean ± SD of Baclofen Pharmacokinetic Parameters Following Oral(10 mg) and Intravenous (5 mg) Administration. 5 mg IV 10 mg oralPharmacokinetic parameter (mean^(a) ± SD) (mean ± SD) C_(max) (ng/mL)310 ± 74 174 ± 16  T_(max) (h)^(b) — 1.0 (0.5-2.0) AUC_(last) (ng ·h/mL)  593 ± 111 878 ± 199 AUC_(D-∞) (ng · h/mL)  707 ± 166 1023 ± 232 AUC_(D-∞)/Dose^(c) (ng · h/mL/mg) 141 ± 33 102 ± 23  Bioavailability (%)— 74 ± 15 T_(1/2) (h) 4.52 ± 1.6 4.03 ± 0.73 Abbreviations: AUC, areaunder the curve; IV, intravenous; SD, standard deviation. ^(a)Meanvalues are presented as arithmetic means ^(b)Median (min, max) reportedfor T_(max). ^(c)Two-tailed P value < .05 (paired t-test performed ondose-normalized area under the curve)

The investigational intravenous formulation was well tolerated. Alltreatment-emergent adverse events were characterized by the investigatoras being mild in severity, and all subjects returned to their baselinevalues within 6 hours of drug administration.

E. Discussion

This example illustrates that absolute oral baclofen bioavailability isabout 75%, indicating that approximately 25% of a 10-mg dose is eithernot absorbed or undergoes first-pass metabolism prior to drug reachingsystemic circulation. This suggests that a smaller intravenous baclofendose can be used when it is substituted for an oral dose. For example,assuming linear kinetics, the total systemic exposure (area under thecurve) after an intravenous dose of 15 mg would be equivalent to thetotal exposure achieved after 20 mg of oral baclofen dose. Thus, thisexample suggest that when intravenous baclofen is substituted for oralbaclofen, an equivalent intravenous dose will be about 75% of the oraldose.

In one embodiment of the invention, a method of converting an oral doseof baclofen to an intravenous dose of baclofen comprises (a) determiningthe oral dose; and (b) multiplying the oral dose by between about 0.45and about 1.0 to determine the intravenous dose. In another embodimentof the invention, a method of converting an oral dose of baclofen to anintravenous dose of baclofen comprises (a) determining the oral dose;and (b) multiplying the oral dose by between about 0.6 and about 0.9 todetermine the intravenous dose. In yet another embodiment of theinvention, a method of converting an oral dose of baclofen to anintravenous dose of baclofen comprises (a) determining the oral dose;and (b) multiplying the oral dose by about 0.75 to determine theintravenous dose.

All publications, patents, and patent applications cited above areincorporated by reference herein as though fully set forth.

It will be apparent to those skilled in the art that many modificationsand equivalents thereof may be made without departing from the spiritand scope of the invention.

1.-26. (canceled)
 27. A pharmaceutical solution comprising: an effectivetherapeutic dose of baclofen dissolved in at least one of normal saline,dextrose solution, Lactated Ringer's solution, or any combinationthereof; and at least one of an anticonvulsant drug, an antispasmodicdrug, an anticholinergic drug, or an antibiotic drug; wherein thesolution comprises baclofen at a concentration of up to about 2.0 mg/mL;wherein the solution is adapted to be intravenously administered to asubject.
 28. The solution of claim 27, wherein the solution is sterile.29. The solution of claim 27, wherein the solution comprises baclofen ata concentration of about 0.5-2.0 mg/mL.
 30. The solution of claim 27,wherein the solution comprises baclofen at a concentration of about0.5-1.0 mg/mL.
 31. The solution of claim 27, wherein the effectivetherapeutic dose of baclofen is between about 0.7 and 0.8 times atherapeutically effective dose of oral baclofen.
 32. The solution ofclaim 31, wherein the effective therapeutic dose of baclofen is about0.74 times the therapeutically effective dose of oral baclofen.
 33. Thesolution of claim 31, wherein the effective therapeutic dose of baclofenis about 0.75 times the therapeutically effective dose of oral baclofen.